Except for members of the Lactobacillus family and Borrelia burgdorferi, virtually all studied organisms from Archaea to man depend on iron for survival. Iron deficiency remains the most prevalent nutritional problem in our country, yet recent identification of the gene responsible for hereditary hemochromatosis indicates that 1 in 20 Caucasians carry the defective allele and thus 1 in 400 may be susceptible to iron overload. Increased knowledge about the factors protecting against iron deficiency and overload is essential to address these significant health problems. The ultimate goal of this project is to utilize the multi-cellular organism C. elegans to elucidate the homeostatic mechanisms regulating the transport and assimilation of iron in man. C. elegans provides a useful multi-cellular model system with the power of genetic manipulation to study iron transport and its homeostasis. Furthermore, the completed sequence of the C. elegans genome allows for the prediction of key genes involved in the transport process and for the rapid identification of those that remain unknown. The purpose of the R21 application is to establish sufficient preliminary data from the study of iron transport and its regulation in C. elegans to generate R01 funding to enable the translation of this information to mammalian systems. The specific aims of the proposal are straightforward: 1) Define the relationships between proteins identified by homology to mammalian counterparts to play a role in iron uptake and its regulation in the nematode; 2) Perform global expression analysis to profile the iron-regulated genome of C. elegans; 3) Use genetic selection to establish transport mutants useful for the elucidation of additional proteins involved in iron import and/or export and the factors that regulate these processes.